TW201902462A - 用於免疫促效劑之新穎投與途徑 - Google Patents
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Abstract
本文揭示包含免疫促效性抗體之液體醫藥製劑之新用途,其產生改良之耐受性/不良事件概況,同時至少維持該免疫促效劑之相同程度之生物活性。
Description
本發明係關於非經腸抗體調配物、具體而言用作免疫促效劑之抗體或抗體片段之皮下(sc)醫藥製劑的領域。
免疫調節抗體提供治療方法且可能用於直接增強抗腫瘤免疫反應或用作抗癌症疫苗之佐劑(Melero, I.等人,Nat Rev Cancer 7, 2007
, 95-106)。免疫促效劑、尤其促效性抗CD40抗體構成該等試劑之一種最有效類別。CD40係在抗原呈遞細胞(APC) (例如樹突狀細胞、B細胞及巨噬細胞)上表現之腫瘤壞死因子超家族之細胞表面成員。使用抗CD40促效劑之臨床前研究表明,利用交聯抗原呈遞細胞(APC)上之抗體觸發CD40可取代通常經由CD40配體提供之CD4輔助T細胞,且有利於CD8效應T細胞之活化以及擴增(Li, F.等人,Science 333
,2011
, 1030-1034)。另外,CD40活化之巨噬細胞亦可發揮直接殺腫瘤功能(Beatty, G. L.等人Science 331
,2011
, 1612-1616;Vonderheide, R. H.等人,Oncoimmunology 2
,2013
, e23033)。CD40促效劑揭示於WO 2003/040170中。
習用地,免疫促效劑之靜脈內(iv)投與通常與不利的不良事件或耐受性概況相關,其可能導致該免疫促效劑之治療效能低於最佳,或甚至中斷治療(例如,參見Vonderheide R. H.等人,Clin Cancer Res 19(5), 2013,
1035-1043)。皮下(sc)投與抗體可用於克服靜脈內抗體調配物所觀察到之一些效應。已知抗體之一些s.c.調配物(Lundin J.等人,Blood 100 (3)
, 2002,2001
, 768-773;Davies A.等人,Lancet Oncol 15(3)
,2014
, 343-352),其中一些商業產品係可用的。然而,大多數該等調配物包含拮抗性抗體,且通常需要特定賦形劑(例如玻尿酸酶)來達成期望效應。仍然需要尋找適用於免疫促效劑之sc投與之新的替代醫藥調配物。
本文揭示之特異性CD40促效劑之醫藥組合物(例如)揭示於WO2003/040170中。
本發明包含包含免疫促效劑之液體醫藥製劑之用途,其用於治療患有癌症或傳染病之患者,其中該液體醫藥製劑係皮下投與,且其中與該相同製劑之其他非經腸投與途徑相比,該皮下投與提供改良之耐受性及至少相等之效能。
本發明進一步包含如上文所述用途,其中免疫促效劑係特異性結合並活化人類CD40之抗體或其抗原結合部分。
本發明進一步包含含有免疫促效劑之液體醫藥製劑,其用於治療癌症或傳染病,其特徵在於其係皮下投與。
本發明進一步包含含有如本文定義之液體醫藥調配物之注射裝置。
本發明進一步包含含有液體醫藥製劑之小瓶、視情況以及根據本發明皮下投與患者之注射裝置的套組。
本發明進一步包含治療患有傳染病或增殖性疾病(例如癌症)之患者之方法,該方法包含皮下投與包含免疫調節劑、具體而言抗CD40抗體之液體醫藥製劑。
序列表
SEQ ID NO 1: 人類CD40 SEQ ID NO 2: 根據本發明之CD40抗體之輕鏈可變域(VL)。 SEQ ID NO 3: 根據本發明之CD40抗體之重鏈可變域(VH)。
具有針對活化免疫細胞(例如CD3 (Topp M.S.等人,Lancet Oncol. 16(1), 2015
, 57-66)、CD28 (Suntharalingam, G.等人,N Engl J Med. 355(10)
,2006
, 1018-28))上之分子之促效功能的單株抗體在靜脈內投與後可導致細胞介素釋放,其可具有劑量限制性。
CD40 (即腫瘤壞死因子受體(TNFR)超家族之成員)經由在抗原呈遞細胞(APC)上表現而係抗腫瘤免疫反應之關鍵調節劑,該等抗原呈遞細胞包括B淋巴球、樹突細胞(DC)及單核球(例如,參見Grewal IS等人,Ann Rev Immunol
,1998
;16:111-35; Van Kooten C等人,J Leukoc. Biol
,2000
;67:2-17;或O'Sullivan B等人,Crit Rev Immunol. 2003
;23(1 2):83-107)。CD40刺激之DC上調抗原處理及呈遞路徑並遷移至淋巴結以活化幼稚T細胞。顯示促效劑CD40抗體可取代CD4+淋巴球之功能,從而導致細胞毒性T淋巴球(CTL)擴增,其能夠清除鼠類模型中確立之淋巴瘤(例如,參見Sotomayor EM等人,Nature Medicine
,1999
;5(7):780-7;Gladue RP等人,Cancer Immunol Immunother
,2011
;60(7):1009-17)。CD40促效劑藉由活化宿主APC觸發免疫刺激,該等宿主APC隨後驅動針對腫瘤之T細胞反應(例如,參見Vonderheide RH,Clin Cancer Res
,2007
;13:1083-8)。
本發明之發明人已發現一種即用型醫藥製劑,其先前已用於i.v.投與,可以不加修改地用於s.c.投與。該製劑之皮下使用導致患者之耐受性及/或不良事件概況改良,同時至少維持或甚至改良免疫促效劑之完全生物活性(NCT02665416、NCT02304393)。維持該免疫促效劑之完全生物活性係(例如)由活化免疫細胞之能力來證實,其引起該等細胞之增殖及活化(基於分別Ki67及CD69在該等細胞(例如CD8 T細胞)中之表現來確定)及/或該等細胞(例如CD20或CD19表現B細胞)自外周血遷移至體內之其他區室。此外,根據本發明之皮下使用導致在一個治療週期內投與更高劑量之該免疫促效劑,因此導致每個治療週期之更高效能及改良之耐受性。因此,在本發明之另一態樣中,本發明人亦根據本發明鑑別CD40抗體之投與之之特定劑量或劑量範圍。
因此,在一個實施例中,本發明包含含有免疫促效劑及醫藥上可接受之載劑之液體醫藥製劑,其用於皮下(sc)投與患有癌症或傳染病之患者,其中該使用之特徵在於與相同醫藥上可接受之載劑中之該相同免疫促效劑的其他非經腸投與途徑、尤其靜脈內(iv)注射相比,改良不良事件概況。包含該免疫促效劑之該液體醫藥製劑之皮下投與維持至少相同或實質上相同之生物活性,如同包含該免疫促效劑之該液體醫藥製劑將靜脈內注射一樣。在本發明之某些實施例中,當與相同醫藥製劑之iv投與相比時,根據本發明sc投與後,該免疫促效劑之生物活性甚至得以改良。
如本文所用「免疫促效劑」與細胞上之受體組合且起始與該受體之天然配體所起始類似或相同之反應或活性。
如本文所用之「CD40促效劑」誘導以下(但不限於)反應中之任一者或全部:B細胞增殖及/或分化;經由諸如ICAM-1、E-選擇素、VC AM及諸如此類等分子之細胞內黏附之上調;促發炎細胞介素(例如IL-1、IL-6、IL-8、IL-12、TNF及諸如此類)之分泌;經由CD40受體藉由諸如以下等途徑之信號轉導:TRAF {例如,TRAF2及/或TRAF3)、MAP激酶(例如NIK (NF-kB誘導激酶))、I-κ B激酶(IKK /.β.)、轉錄因子NF-kB、Ras及MEK/ERK途徑、PI3K AKT途徑、P38 MAPK途徑及諸如此類;藉由諸如XIAP、mcl-1、bcl-x及諸如此類等分子之抗凋亡信號之轉導;B及/或T記憶細胞產生;B細胞抗體產生;B細胞同種型轉換、II類MHC及CD80/86之細胞表面表現上調及諸如此類。
促效劑活***指使用相同之讀出比由不相關之同型對照抗體誘導之平均效應高至少3個標準偏差的促效劑活性(藉由諸如細胞增殖或共刺激分子(例如CD40表現細胞(例如B淋巴球)上之CD80或CD86)之誘導等參數的讀出)。
如本文所用之「CD40促效劑」(或「CD40抗體」)包括任何促效CD40/CD40L相互作用之部分。通常,該等部分將為促效性CD40抗體或促效性CD40L多肽。該等抗體包括(舉例而言)特異性促效CD40/CD40L結合相互作用之人類抗體、嵌合抗體、人類化抗體、雙特異性抗體、scFv及抗體片段。在一個實施例中,促效性CD40抗體將包含嵌合、完全人類或人類化CD40抗體。在另一較佳實施例中,促效性CD40抗體將包含完全人類CD40抗體。
在另一實施例中,如上文所提及之免疫促效劑係CD40促效劑或CD40促效劑之片段。如由根據本發明之CD40促效劑靶向之人類CD40抗原係50 kDa細胞表面醣蛋白,其屬腫瘤壞死因子受體(TNF-R)家族(Stamenkovic等人,EMBO J. 8:1403-10 (1989))。其亦稱為「腫瘤壞死因子受體超家族成員5」。替代名稱包括B細胞表面抗原40、Bp50、CD40L受體、CDw40、CDW40、MGC9013、p50或TNFRSF5。其係例如以UniProt項目號P25942註冊。在一個實施例中,人類CD40抗原具有根據SEQ ID NO: 1之序列(參見表1)。表 1
:人類CD40抗原之蛋白序列
在一個實施例中,人類CD40具有根據SEQ ID NO:1之序列。如本文所用,「結合至人類CD40」或「特異性結合至人類CD40」或「結合至人類CD40者」或「抗CD40抗體」係指抗體以1.0 × 10-8
mol/l或更小之KD
-值、在一個實施例中1.0 × 10-9
mol/l或更小之KD
-值之結合親和性特異性結合至人類CD40抗原。結合親和性係利用標準結合分析(例如表面電漿共振技術(BIAcore®, GE-Healthcare Uppsala, Sweden))測定。因此,如本文所用之「結合及活化人類CD40之抗體」係指抗體以KD為1.0 × 10-8
mol/l或更小(在一個實施例中1.0 × 10-8
mol/l - 1.0 × 10-13
mol/l)、在一個實施例中KD為1.0 × 10-9
mol/l或更小(在一個實施例中1.0 × 10-9
mol/l - 1.0 × 10-13
mol/l)之結合親和性特異性結合至人類CD40抗原。在另一實施例中,根據本發明之抗CD40抗體以4 × 10-10
M或更小之KD
結合至人類CD40。
在本發明之一個實施例中,結合至人類CD40之抗體係促效劑(「CD40促效劑」)。
在一個實施例中,該CD40抗體係IgG2亞類之完全人類抗體。在另一實施例中,該抗體係如WO2003/040170中具體揭示之抗CD40抗體中之任一者。在再一實施例中,根據本發明之CD40促效劑係選自以下之群:根據WO2003/040170命名為3.1.1、7.1.2、10.8.3、15. 1.1、21.4.1、21.2.1、22.1.1、23.5.1、23.25.1、23.29.1及24.2.1之抗體。分泌彼等抗體之雜交瘤已根據Budapest Treaty寄存。寄存號可參見WO2003/040170之段落[0250]。在另一實施例中,根據本發明之CD40抗體本發明包含抗體21.4.1 (ATCC寄存號PTA-3605)之重鏈及輕鏈可變域胺基酸序列。在另一實施例中,根據本發明之CD40抗體由抗體21.4.1 (ATCC寄存號PTA-3605)之重鏈及輕鏈胺基酸序列組成。
在一個實施例中,根據本發明之人類促效性抗CD40抗體包含胺基酸SEQ ID NO: 2之輕鏈可變域及胺基酸SEQ ID NO: 3之重鏈可變域(表2)。表 2
:根據本發明之CD40促效劑之輕鏈(VL)及重鏈(VH)可變域的胺基酸序列.
在另一實施例中,CD40促效劑係IgG2亞類之完全人類抗體,其以4 × 10-10
M或更小之KD
結合至人類CD40;或包含SEQ ID NO:3之VL及SEQ ID NO:4之VH的抗體;或 包含抗體21.4.1 (ATCC寄存號PTA-3605)之重鏈及輕鏈可變域胺基酸序列的抗體。
在另一實施例中,根據本發明之CD40抗體或CD40促效劑係具有INN塞利克單抗之抗體。
本文所用之術語「改良之耐受性」意指與相同液體醫藥製劑之其他非經腸投與途徑(例如靜脈內投與)相比,患者之不良事件較少。術語「不良事件」或「不良事件概況」意指由CD40對細胞之促效作用引起的直接或間接效應,通常非經由表現CD40之免疫細胞釋放細胞介素專門地表現。此概況包括臨床症狀(例如發冷、發熱、低血壓等)以及用於監測器官功能之血清參數之變化(例如肝功能測試及凝血參數)。
本文所用之術語「皮下投與(sc)」意指經由注射入皮下組織投與CD40促效劑,添加或不添加有利於吸收之組分(例如玻尿酸酶)。SC投與包括在同一投藥日分割劑量及投與多個解剖學位點之選擇,且亦包括單次及重複投藥(間隔3-4週)。
如本文所用之「液體醫藥製劑」係藉由混合具有期望純度之該免疫促效劑與一或多種可選「醫藥上可接受之載劑」(Remington's Pharmaceutical Sciences,第16版,Osol, A.編輯(1980))製備呈水溶液或凍乾調配物之形式。本文所用之「醫藥上可接受之載劑」在所用劑量及濃度下通常對接受者無毒,且包括(但不限於):緩衝液,例如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(例如十八烷基二甲基苄基氯化銨;六甲氯銨(hexamethonium chloride);氯化苄烷銨(benzalkonium chloride);苄索氯銨(benzethonium chloride);酚、丁醇或苄醇;對羥基苯甲酸烷基酯,例如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質,例如血清白蛋白、明膠或免疫球蛋白;親水聚合物,例如聚乙烯吡咯啶酮;胺基酸,例如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單糖、雙糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,例如EDTA;糖,例如蔗糖、甘露醇、海藻糖或山梨醇;鹽形成相對離子,例如鈉;金屬錯合物(例如Zn-蛋白質錯合物);及/或非離子表面活性劑,例如聚乙二醇(PEG)。本文之實例性醫藥上可接受之載劑進一步包括間質性藥物分散劑,例如可溶中性活性透明質酸酶醣蛋白(sHASEGP),例如人類可溶性PH-20透明質酸酶醣蛋白,例如rHuPH20 (HYLENEX®, Baxter International, Inc.)。某些實例性sHASEGP及使用方法(包括rHuPH20)闡述於美國專利公開案第2005/0260186號及第2006/0104968號中。在一個態樣中,將sHASEGP與一或多種另外糖胺基多糖酶(例如軟骨素酶)組合。
實例性凍乾抗體調配物闡述於美國專利第6,267,958號中。水性抗體調配物包括闡述於美國專利第6,171,586號及WO2006/044908中之彼等,後一些調配物包括組胺酸-乙酸鹽緩衝液。
欲用於s.c.投與之調配物通常為無菌的。無菌性可藉由(例如)經由無菌過濾膜進行過濾來容易地達成。
在一個實施例中,本發明提供如WO2003/040170中揭示之免疫促效劑CD40抗體21.4.1 (ATCC寄存號PTA-3605),其係以10 mg/ml之濃度於由以下組成之緩衝溶液中製備:20 mM乙酸鈉、140 mM氯化鈉、0.02%聚山梨醇酯80,pH 5.5。液體調配物係於2 mL小瓶中提供,由此含有20 mg/小瓶之量之CD40抗體。此調配物亦揭示於本文中之實例1中。
本發明之醫藥組合物中之免疫促效劑、具體而言CD40促效劑之實際劑量值可變化,以獲得可有效地達成對特定患者之期望治療反應之活性成分量、組合物及投與模式,而對患者無毒(有效量)。所選劑量值將取決於多種藥物動力學因素,包括所用之本發明之特定免疫促效劑的活性、或所治療之患者之年齡、性別、體重、狀況、一般健康狀況及既往病歷以及醫學領域中熟知之類似因素。在一個實施例中,根據本發明之CD40促效劑之劑量係約1至100 mg/ml,或約10至80 mg/ml,或約10至40 mg/ml,或約10至30 mg/ml,或約5至55 mg/ml。在另一實施例中,根據本發明之CD40促效劑之劑量係約5 mg/ml,或約10 mg/ml,或約15 mg/ml,或約20 mg/ml,或約25 mg/ml,或約30 mg/ml,或約35 mg/ml,或約40 mg/ml,或約45 mg/ml,或約50 mg/ml,或約55 mg/ml。
在另一實施例中,CD40抗體係以選自每個治療週期約8mg至48mg、較佳約12mg至約32mg之均一劑量;或以選自每個治療週期14 mg、15 mg、16 mg、17 mg或18 mg之劑量投與。
在另一實施例中,CD40抗體係具有INN塞利克單抗之抗體,且係以每個治療週期16 mg之均一劑量投與。
根據本發明之組合物之pH可在5.0與6.0之間變化。可使用任何生理上可接受之緩衝液以獲得該pH。在一個實施例中,緩衝液係選自琥珀酸鈉或乙酸鈉,具有或無氯化鈉。在另一實施例中,所選緩衝液係以約10 mM至30 mM、尤其約20 mM之量存在,且pH係約5.5。
根據本發明之組合物可含有表面活性劑。在一個實施例中,表面活性劑係非離子表面活性劑。在另一實施例中,表面活性劑係選自泊洛沙姆(Poloxamer)或聚山梨醇酯之群。在另一實施例中,表面活性劑係泊洛沙姆-188或聚山梨醇酯-20或聚山梨醇酯80。根據本發明,表面活性劑係以約0.02至0.1 % (w/v)之濃度存在。在一個實施例中,表面活性劑係以0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09或0.1 % (w/v)之濃度存在。
在本發明之另一實施例中,根據本發明之組合物可視情況含有低溫保護劑及/或抗氧化劑。在一個實施例中,低溫保護劑係糖,尤其蔗糖,且抗氧化劑係甲硫胺酸。低溫保護劑係以約180-300 nM或約240 nM之量存在。抗氧化劑係以約0 mM至20 mM,或約0-10 mM,或約10 mM之量存在。
如本文所用術語「癌症」較佳意指實體腫瘤,例如肺癌、非小細胞肺(NSCL)癌、支氣管肺泡細胞肺癌、骨癌、胰臟癌、皮膚癌、頭或頸癌、表皮或眼內黑色素瘤、子宮癌、卵巢癌、直腸癌、肛區癌、胃癌(stomach cancer)、胃癌(gastric cancer)、結腸癌、乳癌、子宮癌、輸卵管癌、子宮內膜癌、子宮頸癌、***癌、***癌、霍奇金氏病(Hodgkin's Disease)、食道癌、小腸癌、內分泌系統癌症、甲狀腺癌、甲狀旁腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、***癌、膀胱癌、腎臟或輸尿管癌、腎細胞癌、腎盂癌、間皮瘤、肝細胞癌、膽管癌、中樞神經系統(CNS)贅瘤、脊椎腫瘤、腦幹膠質瘤、多形性膠質母細胞瘤、星形細胞瘤、神經鞘瘤、室管膜瘤、髓母細胞瘤、腦脊膜瘤、扁平細胞癌、垂體腺瘤、淋巴瘤、淋巴球性白血病,包括任一上述癌症之難治性型式或一或多種上述癌症之組合。在一個較佳實施例中,該癌症係乳癌、結腸直腸癌、黑色素瘤、頭頸癌、肺癌或***癌。在一個實施例中,該癌症係選自以下之實體腫瘤:乳癌、肺癌、結腸癌、卵巢癌、黑色素瘤癌、膀胱癌、腎癌、腎癌、肝癌、頭頸癌、結腸直腸癌、胰臟癌、胃癌、食管癌、間皮瘤或***癌。在另一實施例中,該癌症係血液腫瘤,例如白血病(例如AML、CLL)、淋巴瘤、骨髓瘤。在再一實施例中,癌症係乳癌、肺癌、結腸癌、結腸直腸癌、胰臟癌、胃癌或***癌。
如本文所用術語「傳染病」意指由諸如細菌、病毒、真菌或寄生蟲等生物體引起之病症。傳染病之具體實例包含(但不限於) B型肝炎病毒(HBV)、C型肝炎病毒(HCV)及/或人類免疫缺失病毒(HIV)。
在一個實施例中,根據本發明之s.c.投與用於預防或治療轉移。
在一個實施例中,根據本發明之s.c.投與用於治療或延遲免疫相關疾病(例如腫瘤免疫性)之進展。
在一個實施例中,根據本發明之s.c.投與用於刺激免疫反應或功能,例如T細胞活性。
如本文所用術語「可變域」(輕鏈可變域VL、重鏈可變域VH)表示每一對直接參與抗體與抗原結合之輕鏈及重鏈域。輕鏈及重鏈可變域具有相同的一般結構,且每一域包含藉由三個「超變區」(或互補決定區,CDR)連接之四個序列高度保守之框架區(FR)。框架區採用β-摺疊構象,且CDR可形成連接β-摺疊結構之環。每一鏈中之CDR藉由框架區保持其三維結構並與另一鏈之CDR一起形成抗原結合位點。抗體之重鏈及輕鏈CDR3區在本發明抗體之結合特異性/親和力方面起尤其重要的作用,且因此提供本發明之又一目標。
術語「抗體之抗原結合部分」在用於本文中時係指抗體之負責抗原結合之胺基酸殘基。抗體之抗原結合部分包含來自「互補決定區」或「CDR」之胺基酸殘基。「框架」或「FR」區係除如本文所定義之超變區殘基外之彼等可變域區。因此,抗體之輕鏈及重鏈可變域自N端至C端包含域FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。特定而言,重鏈之CDR3係對抗原結合貢獻最大且定義抗體之性質之區。CDR及FR區係根據Kabat等人,Sequences of Proteins of Immunological Interest,第5版,Public Health Service, National Institutes of Health, Bethesda, MD (1991)之標準定義及/或來自「超變環」之彼等殘基來確定。
在本發明之一個實施例中,特異性結合及活化人類CD40之抗體之「抗原結合部分」包含抗體21.4.1 (ATCC寄存號PTA-3605)之重鏈及輕鏈可變域之CDR1、CDR2及CDR3。
如本文所用術語「核酸」或「核酸分子」意欲包括DNA分子及RNA分子。核酸分子可為單鏈或雙鏈DNA,但較佳為雙鏈DNA。
如本申請案內所使用之術語「胺基酸」表示天然羧基α-胺基酸之群,其包含丙胺酸(三字母代碼:ala,單字母代碼:A)、精胺酸(arg, R)、天冬醯胺酸(asn, N)、天冬胺酸(asp, D)、半胱胺酸(cys, C)、麩醯胺酸(gln, Q)、麩胺酸(glu, E)、甘胺酸(gly, G)、組胺酸(his, H)、異白胺酸(ile, I)、白胺酸(leu, L)、離胺酸(lys, K)、甲硫胺酸(met, M)、***酸(phe, F)、脯胺酸(pro, P)、絲胺酸(ser, S)、蘇胺酸(thr, T)、色胺酸(trp, W)、酪胺酸(tyr, Y)及纈胺酸(val, V)。
抗體之「Fc部分」並不直接參與抗體與抗原之結合,但展現多種效應物功能。「抗體之Fc部分」係熟習此項技術者所熟知且基於抗體之木瓜蛋白酶裂解定義之術語。抗體或免疫球蛋白根據其重鏈恆定區之胺基酸序列分成以下類別:IgA、IgD、IgE、IgG及IgM,且該等中之若干可進一步分成亞類(同種型),例如IgG1、IgG2、IgG3、及IgG4、IgA1及IgA2。根據重鏈恆定區,不同類別之免疫球蛋白分別稱為α、δ、ε、γ及μ。抗體之Fc部分基於補體活化、C1q結合及Fc受體結合直接參與ADCC (抗體依賴性細胞介導之細胞毒性)及CDC (補體依賴性細胞毒性)。補體活化(CDC)係藉由補體因子C1q與大部分IgG抗體亞類之Fc部分結合來起始。儘管抗體對補體系統之影響取決於某些條件,但與C1q之結合係由Fc部分中之經定義結合位點來引起。該等結合位點為現有技術所知且由以下闡述:例如Boackle, R.J.等人,Nature 282 (1979) 742-743;Lukas, T.J.等人,J. Immunol. 127 (1981) 2555-2560;Brunhouse, R.及Cebra, J.J., Mol. Immunol. 16 (1979) 907-917;Burton, D.R.等人,Nature 288 (1980) 338-344;Thommesen, J.E.等人,Mol. Immunol. 37 (2000) 995-1004;Idusogie, E.E.等人,J. Immunol. 164 (2000) 4178-4184;Hezareh, M.等人,J. Virology 75 (2001) 12161-12168;Morgan, A.等人,Immunology 86 (1995) 319-324;EP 0 307 434。該等結合位點係(例如) L234、L235、D270、N297、E318、K320、K322、P331及P329 (根據Kabat, E.A.之EU索引編號,參見下文)。亞類IgG1、IgG2及IgG3之抗體通常顯示補體活化及C1q及C3結合,而IgG4不活化補體系統且不結合C1q及C3。
在一個實施例中,根據本發明之免疫促效劑,較佳CD40促效劑,係單株抗體。在另一實施例中,根據本發明之免疫促效劑,較佳CD40促效劑,為人類IgG類別(即IgG1,或IgG2,或IgG3,或IgG4亞類)。
在一個實施例中,本文所述之免疫促效劑,較佳CD40促效劑,特徵在於恆定鏈為人類來源。該等恆定鏈為此技術周知且例如由 Kabat, E.A.闡述(參見例如Johnson, G.及Wu, T.T., Nucleic Acids Res. 28 (2000) 214-218)。
本文所述之免疫促效劑,較佳CD40促效劑,較佳係藉由重組方式產生。該等方法已為業內廣泛所知,且包含於原核及真核細胞中表現蛋白質,以及隨後分離抗體多肽,並通常純化至醫藥上可接受之純度。就蛋白質表現而言,藉由標準方法將編碼輕鏈及重鏈或其片段之核酸***表現載體中。在適當原核或真核宿主細胞(例如CHO細胞、NS0細胞、SP2/0細胞、HEK293細胞、COS細胞、酵母或大腸桿菌(E. coli)細胞)中實施表現,且自該等細胞(自上清液或在細胞溶解後)回收抗體。
抗體之重組產生為此技術所熟知且闡述於例如以下綜述文章中:S.C., Protein Expr. Purif. 17 (1999) 183-202;Geisse, S.等人,Protein Expr. Purif. 8 (1996) 271-282;Kaufman, R.J., Mol. Biotechnol. 16 (2000) 151-161;Werner, R.G., Drug Res. 48 (1998) 870-880。
該等抗體可存在於整個細胞中、於細胞溶解物中,或以部分純化或實質上純形式存在。藉由標準技術實施純化以消除其他細胞組分或其他污染物(例如其他細胞核酸或蛋白質),該等標準技術包括鹼/SDS處理、CsCl分帶(banding)、管柱層析、瓊脂糖凝膠電泳及業內熟知之其他技術。參見Ausubel, F.等人編輯,Current Protocols in Molecular Biology, Greene Publishing and Wiley Interscience, New York (1987)。
在NS0細胞中之表現由(例如) Barnes, L.M.等人,Cytotechnology 32 (2000) 109-123;Barnes, L.M.等人,Biotech. Bioeng. 73 (2001) 261-270闡述。瞬時表現由(例如) Durocher, Y.等人,Nucl. Acids. Res. 30 (2002) E9闡述。可變域之選殖由以下文獻闡述:Orlandi, R.等人,Proc. Natl. Acad. Sci. USA 86 (1989) 3833-3837;Carter, P.等人,Proc. Natl. Acad. Sci. USA 89 (1992) 4285-4289;Norderhaug, L.等人,J. Immunol. Methods 204 (1997) 77-87。較佳瞬時表現系統(HEK 293)由以下文獻闡述:Schlaeger, E.-J.及Christensen, K.,Cytotechnology 30 (1999) 71-83及Schlaeger, E.-J., J. Immunol. Methods 194 (1996) 191-199。
將本發明之重鏈及輕鏈可變域與啟動子、轉譯起始、恆定區、3'非轉譯區、多腺苷酸化及轉錄終止之序列組合以形成表現載體構築體。可將重鏈及輕鏈表現構築體組合至單一載體中,共轉染、連續轉染或單獨轉染至宿主細胞中,隨後融合以形成表現兩條鏈之單一宿主細胞。
舉例而言,適用於原核生物之控制序列包括啟動子、視情況操縱子序列及核糖體結合位點。已知真核細胞可利用啟動子、增強子及多聚腺苷酸化信號。
當核酸與另一核酸序列具有功能關係時,該核酸為「可操作地連接的」。舉例而言,若前序列或分泌前導序列之DNA表現為參與多肽分泌之前蛋白,則該前序列或分泌前導序列之DNA可操作地連接至該多肽之DNA;若啟動子或增強子影響編碼序列之轉錄,則該啟動子或增強子可操作地連接至該序列;或若核糖體結合位點之定位有助於轉譯,則該核糖體結合位點可操作地連接至該編碼序列。通常,「可操作地連接」意指所連接之DNA序列係鄰接的,且在分泌前導序列之情形下係鄰接的且位於閱讀框中。然而,增強子無需鄰接。連接係藉由在便捷限制位點接合來完成。若不存在該等位點,則根據習用慣例使用合成寡核苷酸銜接子或連接體。
藉由習用免疫球蛋白純化程序適宜地將單株抗體與培養基分離,該等純化程序係例如蛋白質A-Sepharose、羥基磷灰石層析、凝膠電泳、透析或親和層析。編碼單株抗體之DNA及RNA可使用習用程序容易地分離及測序。雜交瘤細胞可用作該DNA及RNA之來源。一旦分離,可立即將DNA***表現載體中,然後將其轉染至原本不產生免疫球蛋白之宿主細胞(例如HEK 293細胞、CHO細胞或骨髓瘤細胞)中,以在宿主細胞中獲得重組單株抗體之合成。
如本文所用表述「細胞」、「細胞系」及「細胞培養物」可互換使用,且所有該等名稱皆包括子代。因此,詞語「轉化體」及「轉化細胞」包括原代個體細胞及源自其之培養物,而不考慮轉移次數。亦應理解,所有子代之DNA含量可能由於有意或無意突變而不精確相同。本發明包括如在初始轉化細胞中篩選之具有相同功能或生物活性之變體子代。
產生根據本發明使用之特異性CD40促效性抗體之方法亦揭示於WO2003/040170中。
本發明進一步包含治療患有癌症之患者之方法,其特徵在於皮下投與患者治療有效量之根據本發明之包含免疫促效劑、較佳CD40促效劑的液體醫藥製劑。
本發明進一步包含套組,其包含一或多個含有本文揭示之液體調配物中之任一者之小瓶及用於向患者皮下投與該調配物之注射裝置。在此實施例內,根據實例1之液體調配物較佳。
本發明進一步包含醫藥製劑及CD40抗體或如本文定義之促效劑與另一治療劑(較佳抗癌劑)組合、同時或依序之皮下(s.c.)投與的劑量。在一個實施例中,該其他治療劑係選自具有INN阿特珠單抗(atezolizumab)或貝伐珠單抗(bevacizumab)之抗體。該等抗體可根據熟習此項技術者熟知且如(例如)產品Tecentriq®及Avastin®之產品資訊中所述之方法投與。
因此,可藉由以下更具體實施例概述本發明,其中所有變量及術語皆具有下文給出之範圍及/或定義:1. 一種包含免疫促效劑之液體醫藥製劑,其用於治療癌症或傳染病,其中該液體醫藥製劑係皮下投與。 2. 如實施例1使用之液體醫藥製劑,其特徵在於其包含水溶液,該水溶液包含: (a) 約1-100 mg/ml之該免疫促效劑; (b) 約10-30 mM之至少一種提供5至6之pH之緩衝劑;及 (c) 約0.01至0.1 % (w/v)之非離子表面活性劑。 3. 如實施例1或2使用之液體醫藥製劑,其特徵在於其包含水溶液,該水溶液包含: (a) 約10-80 mg/ml之該免疫促效劑; (b) 約20 mM之至少一種提供約5.5之pH之緩衝劑;及 (c) 約0.02 % (w/v)之非離子表面活性劑。 4. 如實施例1至3中任一實施例使用之液體醫藥製劑,其進一步包含約180-300 mM蔗糖及約0-20 mM甲硫胺酸。 5. 如實施例4使用之液體醫藥製劑,其進一步包含約240 mM蔗糖及約0-10 mM甲硫胺酸。 6. 如實施例2至5中任一實施例使用之液體醫藥製劑,其中該緩衝劑係乙酸鹽或琥珀酸鹽緩衝液,例如乙酸鈉或琥珀酸鈉或其組合,視情況其進一步包含約140 mM氯化鈉。 7. 如實施例2至6中任一實施例使用之液體醫藥製劑,其中該非離子表面活性劑係泊洛沙姆188或聚山梨醇酯20或聚山梨醇酯80。 8. 如實施例1至7中任一實施例使用之液體醫藥製劑,其中該免疫促效劑係促效性CD40抗體。 9. 如實施例1至8中任一實施例使用之液體醫藥製劑,其特徵在於其係水溶液,該水溶液含有約10 mg/ml之促效性抗CD40抗體;約20 mM琥珀酸鈉及約0.02 % (w/v)選自聚山梨醇酯20、聚山梨醇酯80或泊洛沙姆188之表面活性劑,pH為約5.5。 10. 如實施例1至9中任一實施例使用之液體醫藥製劑,其中該免疫促效劑係包含SEQ ID NO: 2之輕鏈可變域(VL)及SEQ ID NO: 3之重鏈可變域(VH)的促效性抗CD40抗體。 11. 如實施例10使用之液體醫藥製劑,其中該促效性抗CD40抗體係具有ATCC寄存號PTA-3605之抗體或具有INN塞利克單抗之抗體。 12. 如實施例1至11中任一實施例使用之液體醫藥製劑,其特徵在於該使用包含治療癌症,特定而言實體腫瘤,更特定而言結腸及直腸腺癌、非小細胞肺癌、頭頸部鱗狀細胞癌。 13. 如實施例1至11中任一實施例使用之液體醫藥製劑,其特徵在於該使用包含治療傳染病,尤其B型肝炎病毒(HBV)、C型肝炎病毒(HCV)及/或人類免疫缺失病毒(HIV)。 14. 一種注射裝置,其用於投與如實施例1至13中任一實施例使用之液體醫藥製劑。 15. 一種套組,其包含一或多個含有如實施例1至13中任一實施例使用之液體調配物的小瓶及如實施例14之向患者皮下投與該調配物之注射裝置。 16. 一種如實施例1至11中任一實施例之液體醫藥製劑的用途,其用於治療患有癌症或傳染病之患者,其特徵在於該液體醫藥製劑係皮下投與。 17. 一種如實施例1至11中任一實施例之液體醫藥製劑的用途,其用於製造用於治療癌症或傳染病之藥劑,其特徵在於該液體醫藥製劑係皮下投與。 18. 如實施例17之液體醫藥製劑之用途,其特徵在該液體醫藥製劑用於皮下投與14 mg、15 mg、16 mg、17 mg或18 mg劑量之該免疫促效劑、較佳具有INN塞利克單抗之抗體。 19. 如實施例17或18中任一實施例之液體醫藥製劑之用途,其用於製造用於治療癌症之藥劑。 20. 如實施例19之用途,其進一步包含含有選自阿特珠單抗或貝伐珠單抗之抗體的藥劑作為第二組分,其與塞利克單抗組合、同時或依序一起投與。
實例 實例 1
以下實例闡釋根據本發明之液體醫藥製劑之製備。在此實例中,免疫促效劑係具有INN塞利克單抗之CD40抗體或如WO2003/040170中所揭示之抗體21.4.1 (ATCC寄存號PTA-3605)。以下製備步驟係在無菌條件下應用: 1. 製備含有以下之緩衝溶液(pH 5.5): - 20 mM乙酸鈉, - 140 mM氯化鈉 2. 使用切向流過濾,將步驟1中之CD40抗體濃縮並緩衝更換至緩衝液中。 3. 用聚山梨醇酯-80原液調節緩衝更換產物,以達成0.02% (w/v)聚山梨醇酯-80及10 mg/ml之終產物濃度。
實例 2
: 以下實例闡釋藥物動力學(PK)數據之評價,例如食蟹猴中在單一靜脈內(iv)及皮下(sc)投與後根據實例1之CD40促效劑製劑之最大血漿濃度(Cmax
):
2.1 藉由靜脈內或皮下途徑以0.1 mg/kg、1.0 mg/kg及5.0 mg/kg之劑量值向食蟹猴投藥一次。在投藥前及直至投藥後58天的排定時間自所有動物取全身暴露之樣品:- IV投與:投藥前,投藥後0.08、0.5、1、2、4、6、10、24小時,及然後在第3、4、5、7、9、16、22、29、43及58天。 - SC投與:投藥前,投藥後0.5、1、2、4、6、10、24小時,及然後在第3、4、5、7、9、16、22、29、43及58天。
於室溫下使藥物動力學評估用血樣凝固在管中用於血清製備達60 min。藉由離心(至少10 min.,1200g,+4℃)將凝塊旋轉並在運輸期間儲存於-80℃之冰箱中。使用基於ELECSYS®
2010/e411免疫分析儀平臺(Roche Diagnostics, Germany)之合格之電致化學發光免疫分析(ECLIA)方法測定食蟹猴血清中CD40促效性抗體之濃度。於37℃下將用分析緩衝液預稀釋之樣品與捕獲及檢測分子一起培育9 min。生物素化mAb<H-Fab(κ)>M-IgG-Bi用作捕獲分子,且釕(II)參(聯吡啶基)32+
[Ru(bpy)32+
]標記之mAb<H-Fc-pan>M-R10Z8E9-F(ab‘)2
-BP-Ru小鼠單株抗體用於檢測。添加鏈黴抗生物素蛋白塗覆之磁性微粒,並在37℃下再培育9 min,以容許由於生物素-鏈黴抗生物素蛋白相互作用而形成複合物。將複合物磁性捕獲於電極上,並藉由光倍增器檢測器量測使用共反應物三丙胺(TPA)生成之化學發光信號。對所有研究樣品及陽性或陰性對照樣品進行一式兩份分析,並針對自CD40促效性抗體製備之相應投藥溶液材料進行校準。
2.2 由於sc途徑之延長吸收,s.c.投與導致Cmax
值顯著降低(參見圖 1
)。非線性生物利用度係明顯的,其顯示sc之生物利用度在低(0.1 mg/kg)及中等(1.0 mg/kg)劑量組中介於27%-49%之間,但在高(5.0 mg/kg)劑量組中為100%。非線性生物利用度表明在sc組織及/或引流淋巴系統中可飽和之首過效應。
因此,sc投與容許投與比iv更高之CD40劑量,且藉此容許實現有效劑量而不誘導注射相關反應(IRR)。此乃因iv投與導致極高之Cmax
,其反過來誘導高細胞介素釋放。反過來,sc投與導致更平坦之PK曲線、更低之Cmax
且無IRR。
實例 3 :
此實例證實如臨床試驗中觀察到之與靜脈內(iv)注射相比皮下(sc)投藥之改良之耐受性/不良事件概況(表3)。表 3 :
報告之不良事件(皮下對靜脈內投藥) 1
基於重量投藥0.01-0.3mg/kg,https://www.ncbi.nlm.nih.gov/pubmed/17327609 2
均一劑量投藥1-24mg (等效於IV研究中所用之劑量),https://clinicaltrials.gov/ct2/show/NCT02665416
實例 4 :
此實例證實,當相同組合物自i.v.切換至s.c.投與途徑時,至少維持或甚至改良CD40促效劑之生物活性。藥效學比較表明,相關之T細胞標記中sc後之藥效學與iv後相似或更強(參見圖 2
)。
4.1患者
在基線及自基線研究第4天及第9天自CD40研究NCT02665416及NCT02760797中入選之患者收集全血樣品。對於CD3+、CD8+ T細胞及活化之T細胞(CD3+、CD8+、CD69+)分析,將全血樣品吸入5 mL Cyto-Chex血液收集管(Streck)中。對於增殖(CD3+、CD8+、Ki67+) T細胞分析,將全血樣品吸入4 mL肝素鈉管(BD Vacutainer)中。
4.2組合物及劑量方案
此實例中使用之組合物係如根據實例1獲得。
4.3流式細胞分析
在指示之分析日,在週期之第1天(i.v.)或第2天(s.c.)自接受1、2、4、8、10、12、14、18、24、32、40、48或72 mg CD40注射之患者收集樣品。使用BD FACSCanto II (8色,3激光;Becton Dickinson, Franklin Lakes, NJ, USA)藉由不同組測定淋巴球中之CD19+細胞及CD3+、CD8+ T細胞、增殖CD3+、CD8+、Ki67+ T細胞及活化之CD3+、CD8+、CD69+ T細胞的頻率。
使用以下抗人類抗體(Ab)以鑑別CD19 B細胞群體及CD3+、CD8+ T細胞群體(T、B、NK及單核球分析):抗_CD45_PerCP-Cy5.5 (純系2D1,目錄號332784)、抗CD3_FITC (純系SK7,目錄號345764)、抗CD19_BV421 (純系HIB19,目錄號562440)及抗CD8_APC (純系SK1,目錄號345775)。在不同組中使用以下抗人類Ab以鑑別增殖CD3+、CD8+、Ki67+ T細胞群體:抗CD45_V500 (純系HI30,目錄號560777)、抗CD3_APC (純系UCHT1,目錄號555335)、抗CD8_PE (純系HIT8a,目錄號555635)及抗Ki67 AF-488 (純系B56,目錄號558616)。在不同組中使用以下抗人類Ab以鑑別活化之CD3+、CD8+及CD69+ T細胞群體:抗CD3_AF700 (純系SK7,目錄號344822)、抗CD8_BV605 (純系SK1,目錄號564116)及抗CD69_APC (純系L78,目錄號340560)。所有該等抗體皆由BD Biosciences (San Jose, CA, USA)提供。為了獲得絕對細胞計數結果,應用雙平臺方法(下述計算)。藉由以下門控策略分析特定細胞群體:自白血球群體鑑別CD45+淋巴球,然後門控CD3+ T細胞。在此步驟之後,經由象限門控鑑別CD4+及CD8+ T細胞群體並對Ki67+及CD69+門控CD8+。對於CD19+細胞,自白血球群體鑑別CD45+淋巴球,然後對CD19+ B細胞進行門控。使用FACSDiva TM軟體(BD Biosciences)分析數據。
4.4結果
藉由應用以下計算來計算使用雙平臺之每一可報告參數之絕對細胞計數:絕對細胞計數 = 捕獲事件之 % ( 淋巴 %) x 淋巴球 : 白血球比率 x WBC
-捕獲事件之 % ( 淋巴 %)
:淋巴球門中捕獲事件之%,意欲計算絕對計數之可報告分析物之%- 淋巴球 : 白血球比率 ;
藉由將淋巴球事件計數除以總白血球計數(白血球計數及CD14+計數)計算淋巴球對白血球之比率-WBC
:白血球計數(W
hiteB
lood cellC
ount),來自血液分析儀。
對於增殖CD3+、CD8+、Ki67+ - 以及對於活化之CD3+、CD8+及CD69+ T細胞,使用此雙平臺方法間接計算絕對(細胞/μl)值。藉由前向散射(細胞大小)及側向散射(細胞粒度)測定淋巴球門控。並使用FACSDiva TM軟體(BD Biosciences)分析數據。
皮下及靜脈內CD40投與誘導相似之劑量依賴性B細胞活化,如藉由與預處理值相比第4/5及8/9天外周B細胞百分比之降低所量測(圖 2a
)。
皮下及靜脈內CD40投與誘導T細胞活化,其在週期1第9天sc中具有劑量依賴性,如藉由與預處理值相比第2/5及8/9天增殖之外周CD8+ T細胞百分比之增加所量測(圖 2b
)。
皮下投與途徑中T細胞活化之誘導遵循非線性劑量依賴性。以16 mg之劑量實現T細胞活化之最有效誘導,皮下投與(圖 3
)。
實例 5
此實例提供可根據本發明製備及使用之其他液體醫藥製劑。類似於實例1中揭示之方法,可在無菌條件下根據本發明製備以下液體醫藥製劑。免疫促效劑係如實例1中所述,且可以1-100 mg/ml之量存在。 1. 製備含有以下之緩衝溶液(pH 5至6): - 10-30 mM琥珀酸鈉,及視情況 - 140 mM氯化鈉 2. 使用切向流過濾,將步驟1中之CD40抗體濃縮並緩衝更換至緩衝液中; 3. 用180-300 mM蔗糖、0.02-0.1 % (w/v)泊洛沙姆-188或聚山梨醇酯-20及0-20 mM甲硫胺酸調節緩衝更換產物,以達成1-100 mg/ml之終產物濃度(參見表4)。表 4
:特異性CD40 s.c.組成
圖 1 :
猴中根據本發明iv及sc投與之PK數據(Cmax
)的比較。圖 2 :
與靜脈內投與相比,藉由皮下投與維持至少相同生物活性,如藉由以下各項所證實:(a)
與靜脈內投與相比,皮下投與之後B細胞活化;(b)
與靜脈內投與相比,皮下投與之後T細胞活化。圖 3 :
塞利克單抗(selicrelumab)劑量對表現CD69之T細胞之活化的效應。
Claims (19)
- 一種包含免疫促效劑之液體醫藥製劑,其用於治療癌症或傳染病,其中該液體醫藥製劑係皮下投與。
- 如請求項1之液體醫藥製劑,其包含水溶液,該水溶液包含: (a) 約1-100 mg/ml之該免疫促效劑; (b) 約10-30 mM之至少一種提供pH 5至6之緩衝劑;及 (c) 約0.01至0.1 % (w/v)之非離子表面活性劑。
- 如請求項1或2之液體醫藥製劑,其包含水溶液,該水溶液包含: (a) 約10-80 mg/ml之該免疫促效劑; (b) 約20 mM之至少一種提供pH約5.5之緩衝劑;及 (c) 約0.02 % (w/v)之非離子表面活性劑。
- 如請求項1或2之液體醫藥製劑,其進一步包含約180-300 mM蔗糖及約0-20 mM甲硫胺酸。
- 如請求項4之液體醫藥製劑,其進一步包含約240 mM蔗糖及約0-10 mM甲硫胺酸。
- 如請求項2之液體醫藥製劑,其中該緩衝劑係乙酸鹽或琥珀酸鹽緩衝液,例如乙酸鈉或琥珀酸鈉或其組合,視情況進一步包含約140 mM氯化鈉。
- 如請求項2之液體醫藥製劑,其中該非離子表面活性劑係泊洛沙姆188 (Poloxamer 188)或聚山梨醇酯20或聚山梨醇酯80。
- 2、6及7中任一項之液體醫藥製劑,其中該免疫促效劑係促效性CD40抗體。
- 2、6及7中任一項之液體醫藥製劑,其係水溶液,該水溶液含有約10 mg/ml之促效性抗CD40抗體;約20 mM琥珀酸鈉及約0.02 % (w/v)選自聚山梨醇酯20、聚山梨醇酯80或泊洛沙姆188之表面活性劑,pH約5.5。
- 2、6及7中任一項之液體醫藥製劑,其中該免疫促效劑係促效性抗CD40抗體,其包含SEQ ID NO: 2之輕鏈可變域(VL)及SEQ ID NO: 3之重鏈可變域(VH)。
- 如請求項10之液體醫藥製劑,其中該促效性抗CD40抗體係具有ATCC寄存號PTA-3605之抗體或具有INN塞利克單抗(selicrelumab)之抗體。
- 2、6及7中任一項之液體醫藥製劑,其中該使用係治療癌症,特定而言實體腫瘤,更特定而言結腸及直腸腺癌、非小細胞肺癌、頭頸部鱗狀細胞癌。
- 2、6及7中任一項之液體醫藥製劑,其中該使用係治療傳染病,尤其B型肝炎病毒(HBV)、C型肝炎病毒(HCV)及/或人類免疫缺失病毒(HIV)。
- 一種注射裝置,其用於投與如請求項1至13中任一項之液體醫藥製劑。
- 一種套組,其包含一或多個含有如請求項1至13中任一項之液體醫藥製劑的小瓶及如請求項14之用於向患者皮下投與該液體醫藥製劑之注射裝置。
- 一種如請求項1至11中任一項之液體醫藥製劑的用途,其用於製造用於治療癌症或傳染病之藥劑,其特徵在於該液體醫藥製劑係皮下投與。
- 如請求項16之用途,其中該液體醫藥製劑用於皮下投與14 mg、15 mg、16 mg、17 mg或18 mg劑量之該免疫促效劑、較佳具有INN塞利克單抗之抗體。
- 如請求項16或17之用途,其中該藥劑用於治療癌症。
- 如請求項18之用途,其中該藥劑進一步包含作為第二組分之包含選自阿特珠單抗(atezolizumab)或貝伐珠單抗(bevacizumab)之抗體的藥劑,用於與塞利克單抗一起組合、同時或依序投與。
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EP17174306.5 | 2017-06-02 | ||
EP17174306 | 2017-06-02 | ||
EP17176540.7 | 2017-06-19 | ||
EP17176540.7A EP3418302A1 (en) | 2017-06-19 | 2017-06-19 | Administration routes for immune agonists |
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EP (1) | EP3630827A1 (zh) |
JP (1) | JP2020521788A (zh) |
CN (1) | CN110506058A (zh) |
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DE3883899T3 (de) | 1987-03-18 | 1999-04-22 | Sb2 Inc | Geänderte antikörper. |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
AR039067A1 (es) * | 2001-11-09 | 2005-02-09 | Pfizer Prod Inc | Anticuerpos para cd40 |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
US20050136055A1 (en) * | 2003-12-22 | 2005-06-23 | Pfizer Inc | CD40 antibody formulation and methods |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
AU2009286247A1 (en) * | 2008-08-29 | 2010-03-04 | Academisch Ziekenhuis Leiden H.O.D.N. Lumc | Delivery of a CD40 agonist to a tumor draining lymph node of a subject |
US9345661B2 (en) * | 2009-07-31 | 2016-05-24 | Genentech, Inc. | Subcutaneous anti-HER2 antibody formulations and uses thereof |
SG182304A1 (en) * | 2009-12-29 | 2012-08-30 | Hoffmann La Roche | Antibody formulation |
AR083847A1 (es) * | 2010-11-15 | 2013-03-27 | Novartis Ag | Variantes de fc (fragmento constante) silenciosas de los anticuerpos anti-cd40 |
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- 2018-05-31 TW TW107118607A patent/TW201902462A/zh unknown
- 2018-05-31 CN CN201880020417.0A patent/CN110506058A/zh active Pending
- 2018-05-31 EP EP18727804.9A patent/EP3630827A1/en not_active Withdrawn
- 2018-05-31 WO PCT/EP2018/064320 patent/WO2018220100A1/en active Application Filing
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EP3630827A1 (en) | 2020-04-08 |
JP2020521788A (ja) | 2020-07-27 |
CN110506058A (zh) | 2019-11-26 |
US20200188296A1 (en) | 2020-06-18 |
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